The composition containing proanthocyanidin oligomer obtained according to the invention can be used in food products, health food products, foods for specified health use, cosmetic products and medical products. Especially, the composition is useful as composition for health food products and medical products for prevention of lifestyle-related diseases caused by generation of reactive oxygen species, prevention and treatment of brain diseases or prevention of aging.
Owing to excessive fat intake due to changes in our eating habits, increased exposure to UV rays due to changing environment, ozone depletion and the like, increase in environmental pollutants and the like, incidence rates of so-called lifestyle-related diseases such as hyperlipemia, hypercholesteremia, high pressure, diabetes and cancers are increasing and the number of patients with allergies or with brain diseases such as dementia is also increasing. There is concern that the number of patients with dementia or Alzheimer's syndromes will be increasing in the future with rapid aging of the society. Involvement of reactive oxygen species generated in vivo has been pointed out as factors contributing to these diseases. (Bioorganic & Medicinal Chemistry, Vol. 10 (2002), p.p. 2497-2509, Non-Patent Document 1). However, since perfect technology for suppressing or controlling generation of reactive oxygen species has not been developed yet, there has not been established a sufficiently sure medical technology useful for treating and preventing lifestyle-related diseases, brain diseases and the like.
Recently, natural substances present in plants and exhibiting physiological activities, especially, compounds of polyphenols have been attracting attentions. Polyphenols, which are generally contained in teas, vegetables, fruits, herbs and the like, can be expected to be ingested as food and beverages for a long period of time and serve as treatment/prevention agent free of side effects.
Polyphenol compounds, plant secondary metabolites, which universally exist in the plant world in large quantity and are known to exhibit various physiological activities, attracted attention in the fields of pharmaceuticals and phytochemistry in old times and recently have been drawing attention in the field of health food. For example, tea polyphenols, especially catechins are known to have a wide range of physiological activities such as antibiotic properties, antiviral action, antimutagenic property, antioxidation effect, blood-pressure increase suppression, property of reducing cholesterol in the blood, antidecay property, antiallergic activity, improvement of enteric flora, odor eliminating activity and the like.
Among polyphenols, proanthocyanidins are contained in a wider range of plants. In order for proanthocyanidins to exhibit various physiological activities, proanthocyanidin compound needs to be absorbed into the living body by the gastrointestinal tract. However, molecular weights of proanthocyanidins are generally said to be on the order of several thousands to several tens of thousands. Substance having such a large molecular weight is difficult to be absorbed by the gastrointestinal tract and in many cases, even if it is ingested, it is not absorbed in the living body and not used as nutrition.
The term “proanthocyanidins”, is a generic name for procyanidin, prodelphinidin, propelargonidin and the like of polymers of dimer, trimer, tetramer, decamer or higher oligomers having as constituent unit flavan-3-ol (also referred to as catechins) and those with gallic acid esterified thereto, and stereoisomers thereof, which are polyphenol compounds generating anthocyanidins through acid treatment. The constituent units are bonded to each other through carbon-carbon bond between the 4-position and 8-position of the carbon skeleton or between the 4-position and 6-position, or sometimes through ether bond between the 2-position and 7-position in addition to the carbon-carbon bond.
Proanthocyanidin has an excellent antioxidative effect (Arch. Biochem. Biophys., Vol. 374, p.p. 347-355, 2000: Non-Patent Document 2), and moreover, since it has other effects such as improvement of blood flow, antistress action, antihypertensive efficacy, antibiotic effect, antitumor effect, anticataract activity and antidiarrheic effect, it has been used as a naturally-derived substance having a health-maintaining effect.
Proanthocyanidins are isolated as mixture from pine bark, immature apple fruit, grape seeds and the like and now, are blended in beverages, confectioneries, health foods, cosmetic products, hair-growth drugs and the like which are commercially available.
In many plants containing proanthocyanidin, various proanthocyanidins from those having a low polymerization degree to those having a high molecular weight are contained as mixture, and many of them are plants mainly containing proanthocyanidins of high polymerization degree such as persimmon, banana and Chinese quince. However, among proanthocyanidins, a proanthocyanidin polymer having a high polymerization degree is said to be inferior in pharmacological activities to proanthocyanidin oligomers having polymerization degree of 2 to 4 due to its poorabsorbability from the intestine. Also, it is preferable that such a proanthocyanidin polymer, having strong astringency and poor solubility in water, be eliminated when the plant is used in food products (Free Radical Res., Vol. 29, p.p. 351-358, 1998: Non-Patent Document 3). Based on these facts, proanthocyanidin oligomer having a polymerization degree of 2 to 4 have been attracting attention as having excellent health-maintaining effect and those derived from pine bark are used in beverages and health foods.
In order to obtain only proanthocyanidin from plant extract, absorption method (see, for example, H06-49053: Patent Document 1) and the like are employed. But it is difficult to isolate those different in polymerization degrees. In order to obtain only proanthocyanidin oligomers of polymerization degree 2 to 4, solvent partition method using ethyl acetate, solid-phase extraction method with methyl acetate and chromatography method (PCT Publication WO00/64883: Patent Document 2), chitin absorption method (PCT Publication WO03/091237: Patent Document 3) and the like are employed for isolate only low molecular weight proanthocyanidins through extraction. However, in these methods, a large amount of high molecular weight proanthocyanidin polymers is discarded, which is disadvantageous in terms of yield.
As an alternative method replacing the methods isolating proanthocyanidin oligomers of polymerization degree 2 to 4 from plants containing proanthocyanidin polymers, the present inventors previously proposed a method of reacting proanthocyanidin polymer-containing material with SH-containing compound such as cysteine in an acidic solution to reduce the molecular weight of the proanthocyanidin oligomer (PCT Publication WO2004/103988: Patent Document 4). According to the method, proanthocyanidin oligomer having the cysteine bonded thereto to thereby reduce the molecular weight and be excellent in systemic absorption can be obtained. It has been confirmed that the proanthocyanidin oligomer has no toxicity and can be used safely. However, at present, in some countries (including Japan), there is a problem that strict procedures are required for obtaining approval of uses of health food products containing proanthocyanidin having cysteine attached thereto which is non-natural chemical substance.    [Patent Document 1] Japanese Patent Application Laid-Open No. H06-49053.    [Patent Document 2] PCT Publication No. WO00/64883    [Patent Document 3] PCT Publication No. WO03/091237    [Patent Document 4] PCT Publication No. WO2004/103988    [Non-Patent Document 1] Bioorganic & Medicinal Chemistry, Vol. 10 (2002), p.p. 2497-2509    [Non-Patent Document 2] Arch. Biochem. Biophys., Vol. 374, p.p. 347-355, 2000    [Non-Patent Document 3] Free Radical Res., Vol. 29, p.p. 351-358, 1998